Reduction of body temperature (hypothermia) is a potent neuroprotective approach against damages occurring in various situations such as brain ischemia associated with stroke, cardiac arrest or neonatal ischemia, seizures, severe traumatic brain and spinal cord injuries, or heart surgeries. Reduction of hyperthermia to normothermia is also warranted in pathological situations with elevated body temperature (such as intracranial hypertension (ICH), ischemic or hemorrhagic stroke, traumatic brain injury (TBI), sepsis or any viral, bacterial or parasitic infection associated with fever).
Physical approaches for reducing body temperature have been employed in the art which involve either external methods, such as cooling material or treatment (e.g., cooling blankets, ice baths, etc.) or internal methods (e.g., cooling probes, infusion of cold fluids, etc.), or both. These physical approaches, however, are difficult to implement, expensive, may have delayed onset of action and/or transient effect, and may induce undesirable side effects such as shivering that necessitate administration of additional treatments, including paralytic or sedative agents.
Pharmacological approaches have been suggested, which essentially use neurotensin or analogs thereof. Neurotensin (NT) is a linear tridecapeptide with the amino acid sequence pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH. In mammals endogenous NT is mainly expressed in the CNS where it acts as a neurotransmitter and neuromodulator interacting with dopaminergic systems. NT is also expressed in peripheral tissues, mainly in the gastrointestinal tract, where it plays a role in gut motility. In addition, deregulation of the NT system has been implicated in the pathophysiology of many neuropsychiatric diseases as well as several cancers. When administered directly into the brain or the spinal cord, NT exerts a potent μ-independent antinociceptive effect and hypothermia. Although clinical use of NT could provide an interesting and innovative means to treat many pathophysiological conditions, it is hampered by a very rapid proteolytic cleavage in plasma upon systemic administration. Moreover its poor blood-brain barrier (BBB) permeability hampers its therapeutic potential, unless administered directly into the brain or the spinal cord. Therefore, medicinal chemistry methods allowing the design of neurotensin-based compounds able to elicit central activity upon systemic administration are needed. It has been proposed to either design neurotensin analogs and/or to conjugate neurotensin or its analogs to delivery agents such as antibodies (WO2011/127580) or transport peptides (WO2010/063122).
However, there is a need in the art for neurotensin-based pharmacological agents with improved efficacy and safety profiles, including a rapid onset of action and a biological activity in different pathophysiological conditions, including hyperthermia, excitotoxic processes, neuroinflammation, and convulsions, as well as pain.